Drug addiction is a chronic and relapsing disorder associated with significant costs to both affected individuals and society at large. The neurotransmitters and neurological circuits involved in the process of addiction show long-lasting drug-induced adaptations, believed to result from persistent changes in gene expression. The long-term goal of this project is to identify novel targets for the pharmacotherapy of drug addiction by expanding our knowledge of the molecular mechanisms underlying addiction. A relatively small number of midbrain dopamine (DA)-synthesizing neurons play an enabling role for all drugs of abuse. The important contribution of DA neurons to both the positive and negative reinforcing features of psychostimulant abuse provides a compelling rationale for the further molecular characterization of these neurons in the drug-exposed brain. In this discovery- driven project, we will determine, for the very first time, a comprehensive profile of midbrain gene expression in human cocaine abusers. In Specific Aim 1, we will use high-throughput expression microarray analysis to identify changes in gene expression that are associated with cocaine abuse. In Specific Aim 2, we will investigate specific genes and gene pathways emerging from the determination of cocaine-induced changes in gene expression. Aim 2 will be accomplished using exhaustive bioinformatic analysis of the dataset generated in Aim 1, coupled with experimental validation and cellular localization and quantification of selected transcripts and proteins. Overall, the experiments proposed in Specific Aims 1 and 2 will provide important clues regarding the neuroplasticity in gene and gene network expression that form the molecular bases for cocaine addiction, ultimately providing novel targets for the treatment of drug addiction. PUBLIC HEALTH RELEVANCE: Drug addiction is associated with significant costs to both affected individuals and society at large. The persistence of drug craving and the likelihood of relapse seem to be due to long- lasting changes in the extent to which many genes are turned on or off within critical regions of the brain. This project will reveal for the first time a complete picture of gene activity in one such area by studying the brains of individuals dying of cocaine abuse, with the goal of identifying new targets for the treatment of drug addiction.